Sulfonyl-urethanes and a process for preparing them



V isocyanate.

nited States atcnt OfiEice 2,990,326 Patented June 27, 1961 2,990,326 SULFONYL-URETHANES AND A PROCESS FOR PREPARING THEM Walter Aumnller, Gerhard Korger, Rudi Weyer, and

Wolf-Helmut Wagner, all of Frankfurt am Mam, Germany, assign'ors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main, Germany, a corporation of Germany No Drawing. Filed July 8, 1958, Ser. No. 747,114 Claims priority, application Germany July 9, 1957 7 Claims. (Cl. 167-515) wherein R represents a phenyl radical in which one or two hydrogen atoms can be substituted by alkyl or alkoxy groups with at most six carbon atoms or by halogen atoms, or a naphthyl-(2), a 5,6,7,8-tetra-hydronaphthy1- (2), a 4-phenoxy-benzene, a 4-diphenyl radical or an alkyl, cycloalkyl or cycloalkyl-alkyl radical containing from 3 to 8 carbon atoms, with aliphatic alcohols containing from 4 to 8 carbon atoms or with araliphatic alcohols whose alkyl group contains from 2 to 4 carbon atoms, or by reesterifying correspondingly substituted sulfonyl-urethanes derived from other alcohols with aliphatic alcohols containing 4 to 8 carbon atoms or with araliphatic alcohols whose alkylene-group contains from 2 to 4 carbon atoms, or by splitting correspondingly substituted sulfonyl-ureas whose free amino group is disubstituted with aliphatic alcohols containing from 4 to 8 carbon atoms or with araliphatic alcohols whose alkylene group contains from 2 to 4 carbon atoms, or by reacting correspondingly substituted sulfonamides, preferably in the form of their alkali metal salts, with halogeno-formic acid esters derived from aliphatic alcohols containing from 4 to 8 carbon atoms or from araliphatic alcohols whose alkylene-group contains from 2 to 4 carbon atoms; other compounds which in the course of the reaction react like isocyanates being likewise suitable for carrying out the reaction.

Now we have found that sulfonyl-urethanes showing a special efiiciency against Coccidae, for instance Eimeria tenella, can be prepared by treating sulfonyl-isocyanates of the general formula RSO --NCO, in which R represents a phenyl radical wherein one or two hydrogen atoms may be substituted by alkyl or alkoxy groups containing up to 6 carbon atoms, or by halogen atoms, or represents a naphthyl-(2)-, or a 5,6,7,8-tetrahydronaphthyl-(Z) radical, a phenylalkyl radical containing up to carbon atoms, a 4-phenoxybenzene or a 4-diphenylradical or an alkyl, cycloalkyl, or cycloalkyl-alkyl radical containing up to 8 carbon atoms with low-molecular ahydroxy-B-alkoxy-ethanes, other compounds which in the course of the reaction react like such isocyanates being likewise allowed for carrying out the reaction, or by reesterifying correspondingly substituted sulfonyl-urethanes derived from other alcohols with low molecular a-hy- 2 droxy-fi-alkoxy-ethanes or by splitting correspondingly substituted sulfonyl-ureas of the general formula RSO2-NH-CON'Hg or such of the general formula RSO -NH-CONHR in which R is an aliphatic, aromatic or a mixed aliphaticaromatic acyl radical, or sulfonyl ureas of the general formula RSO -NHCO--N in which the N'- atom is disubstituted, with a-hydroxy-fi-alkoxy-ethanes or by reacting correspondingly substituted sulfonamides, preferably in the form of their alkali metal salts with halogeno-formic esters derived from low-molecular cchydroxy-B-alkoxy-ethanes.

In contradistinction to the aboveanentioned compounds which have already been proposed the sulfonylurethanes of the formula compounds substituted in metaor para-position. There in which R has the meaning given above, surprisingly do not exhibit any or only an insignificant blood sugar lowering effect and, therefore, do not afiect the metabolism of carbohydrates of the animals in the sense of the oral antidiabetics.

As starting substances according to the process of the present invention there enter into consideration in addition to the unsubstituted compound such benzene-sulfonamides as contain one or two straight-chained or branched alkylor alkoxy-groups containing up to 6 carbon atoms and/or halogen atoms. There are mentioned for instance: ortho-toluene-sulfonamide, meta-toluene sulfonamide, para-toluene-sulfonarnide, ortho-ethyl-benzene-sulfonamide, meta-ethyl-benzene-sulfonamide, paraethyl-benzenesulfonamide, ortho-, metaand para-n-propyl-benzene-sulfonamide, ortho-, metaand para-isopropyl-sulfonamide, furthermore corresponding ontho-, metaand para-alkoxy-benzene-sulfonamides, such as orthomethoxy benzene sulfonamide, meta-methoxy-benzenesulfonamide, para-methoxy benzene-sulfonamide, dialkylbenzene-sulfonamides, dialkoxy benzene sulfonamides,

.alkyl alkoxy-sulfonamides, monohalogen-benzene-sulfonamide, dihalogen-benzene-sulfonamide, as well as halogeno-alkyl-benzene-sulfonamides or halogeno-alkoxybenzene-sulfonamides. Particularly, there are. suitable can likewise be used straight-chained or ramified alkylsulfonamides such as n-propane-sulfonamide, isopropanesulfonamide, n-butane-sulfonamide, isobutane-sulfonamide, sec.-b-utane-sulfonamide, ter-t.-butane-sulfonamide, 3-methyl-butane-sulfonamide, n-hexane-sulfonamide, nheptane-sulfonamide, n-octane-sulfonamide, cycloalkylsulfonamides e.g. cyclopentane sulfonamide, 'cyclohexanesulfonamide, cycloheptane-sulfonamide, cycloalkylalkylsulfonamides, such as cyclohexyl-methane-sulfonamide,

furthermore naphthyl-(2)-sulfonamide, or 5,6,7,8-tetrahydro-naphthyl-(Z)-sulfonarnide or 4-phenoXy-benzenesulfonamide, 4-diphenyl-sulfonamide and w-benzyl-sulfonamide. Instead of the aforementioned sulfonamides there can also be used as starting substances the corresponding sulfonyl-isocyanates and sulfonyl-carbarnic acid halides. Finally, there come into consideration corresponding sulfonyl-urethanes, particularly the methylor ethylurethanes which can be reesten'fied by means of a-hydroxy-B-alkoXy-ethanes. Furthermore can be used as starting materials: benzene-sulfonylureas containing in the benzene nucleus one or two straight-chained or branched alkyl or alkoxy-groups containing up to 6 carbon atoms and/or halogen atoms. There are mentioned for example: ortho-, metaand para-toluene-sulfonylurea, ortho-, metaand para-ethyl-benzene-sulfonylurea, ortho-, meta. and para-propyl-benzene-sulfonylurea,

ortho-, metaand para-isopropyl-benzene-sulfonylurea,

furthenmore corresponding ortho-, metaand para-alkoxybeii'zene' s'ulfonylureas, such as'ortho-g. meta= and-paramethoxy benzene-sulfonylurea, dialkyl benzene-sulfonyhureas, dialkoxy-benzene-sulfonylnreas, v alkyl-alkoxy-benzene sulfonylureas, mono -halogeno benzene-sulfonylureas, dihalogeuo-benzene-sulfonylureas. There'canlike wise be used straight-chained or branched alkane-sulfonylureas such as propane sulforiylurea, isopropanesulfonylurea, .butane-sulfonylurea, isobutane-sulfonylurea, 3-niethylmethane-sulfonylurea, hexane-sulfonylurea, heptahe-sulfonylurea, octane sulfonylurea; cycloalkane-sulfonylurea, cycloalkylalkane-sulfonylureas, suchas cyclo heiiyl-methane-sulfonylureas, likewise naphthalene-Z-sulfonylurea, or 5,6,7,8-tetrahydro-naphthalene (2) -sulfonyliirea'. o'r 4'-phenoxy-benzene-sulfonylurea or 4-diphenylsulfonylureas and w-benzyl-sulfonylurea. Furthermore, there can advantageously be used corresponding N- sulfonyl-N acyl-ureas, as acyl radicals being suitable especially low fatty acid groups such the acetyl-group, the propionyl-group, the butyryl-group, as well as aromatic carboxylic ra mined aliphatic/ aromatic carboxylic radicals, for instance the phenacetyl radical. As starting substances there can he. mentioned for example the following N-sulfonyl-N- acylu're'a'sz N-benzene sulfOnyl-N-acetyl-(propionyl-bm tyryl)-urea, N-(4-methyl benzene sulfonyl) -N-acety1- (propionyl-butyryD-urea, N-(4 isopropyl benzene-sulfonyl) N-aC'etYl-(propiOnyl butyryl) -urea, N-(4 chlorohenzene sul fouyl) -N'-acetylpropionyl butyryl) -urea, N-

V 4-methyl-3-methoxy 'benzenesulfonyl) -N-acety1-urea, V

furthermore straight-chained or branched alkane-sulfonyla'c'yliirea's, for instance N butane-sulfonyl-N-acetyl-urea,

as wen as cycloaliphatic sulfonyl-acylureas, such as N- cyclOheXane N aCetyI-uIBa and the like. .lfor the reaction withthe above-mentioned compounds :ther'e. are,nsed a-hydroxy-fl-alkoxy-ethanes or the halo- 'genoforinic esters of formic acid-B-alkoxyethyl-ester.

these compounds such as chloro- As alkoxy-groups the compounds may contain for example methoxy, ethoxy, prop'o'x'y and butoxy groups/the two last-mentioned groups can also be branched. The methoxy-group is particularly suited (glycol-monomethyl-cther) n The reaction is carried out in the usual manner. The .reesterification is favorably carried out in the presence of Tcataly'ticjally activetertiary organic bases, alkali metal hydroxides or alkali metal alcoholates. When starting from corresponding sulfonamides these are favorably reacted in the form of their alkali metal salts with the corresponding halogeno-formic esters.

The, reaction of corresponding sulfonylureas is advanureas are heated for some hours under reflux with an excess of for instance glycol-monomethyl-ether. Substances v which promote the reaction can be added, for instance glacial acetic acid. It is likewise possible to products of the sulfonylureas which are obtained by heating to boil corresponding sulfonarnides, suitably in the form of their alkali rnetal salts with urea in a solution of glycol-monomethyl-ether.

, The products of the invention form well crystallizing alkali metal salts, in particular sodium salts which can easily be purified which quality is much appreciated for the administration of the products, the more so as these salts are characterized by a large resistance and a good solubility in water with nearly neutral reaction.

The products of the invention which are favorably used in the form of their salts but also in the presence of substances which cause salt formation are valuable medicafr'nents'fforveterinary medicine and serve for combating obtain the the hickeh (poultry) coccidiosis.

The compounds obtaife'd according to the invention 'cals, eg the benzoyl radical, or

tageously carried out in such a manner that the sulfonylinvention by using intermediarily formed cidiosis. An action on bacteria does not take place. Therefore, a resistance of the intestinal bacteria against sulfonamides is not developed.

Inthe following. test report the efliciency of N-(4- methyl b'enzene-sulfonyD B-methoxyethyl) -urethane and related urethanes is shown by application by means of the oesophageal sound'and by drinking water tests for therapeutic purposes in chickens.

TABLE 1 A-ppliddiion by oesophagal sound for prophylaxis Average increase in weight at test end, grams Dose, grams/ kilogram Surviving total Preparation 7 number 01 N (4 methylbenzene sulfonyl) (,B-methoxyetlayD-urethane.

TABLE 2 Drinking water test for therapeutic purposes Concentration of N-( tmethyl-benzeue-sulonyl)-(fl-methoxyethyD-urethaue in drinking Water, percent Average increase in weight at the end of test, grams Surviving total number MNN The tests were carried out in chickens experimentally infected ('Eimeria tenel la). In each test all untreated infected control animals (not shown in the table) died. When the disease reached its maximum development (4-5 days following the infection) the animals were given for 3 days any desired amount of water in which the preparation in-the form of its sodium salt was dissolved in the indicated concentration. The surviving total number" constitutes the number of surviving animals 10-12 days after starting the test and referred to the total number of test animals treated. The autopsy carried out in V e'ach'case proved the healing of these animals.

' thoughit is known to use The products of the present inventionare of special importance as anti-coccidiosis agents, since their easily soluble alkali metal salts with tetracycline base or tetracycline hydrochloride; or tetracycline derivatives, for instance pyrrolidin'o-methyltetracycline in combination and if necessary with addition of substances delaying the oxidation of tetracycline, such as sodium-cyanosulfitc, can be added to the drinking water of the animals. The concentrations may amount for example to 0.2O.3% of sulfonyl-urethane and 0.01 to 0.03% of tetracycline. A1-

tetra'cycline as an agent against c'o'ccidiosi's, tests with drinking water surprisingly showed that for instance when using an aqueous solution of 0.2% of N (4 -'methyl benzene sul'fonyl) (B -methoxyethyl) -u'ret;h'aneand 0. 02% of tetracycline-hydrochloride degree which exceeded. the additive efliciency of the two components, since the increased dose of each component per se did not lead to a better therapeutic result.

TABLE 3 Combined tests Concentration in drinking water Average increase in weight at the end of test, grams of N-(4-methyl-benzenesulfonyl)-(B-methoxyethyl) -urethane, percent of tetracycline, percent Surviving total number The tests were carried out in chickens experimentally infected (Eimeria tenella). 'In each test all untreated infected control animals (not shown in the table) died. When the disease reached its maximum (4-5 days following the infection) the animals were given for three days any desired amount of water in which the sulfonylurethane in the form of its sodium salt was dissolved in the indicated concentration. (The surviving total number constitutes the number of surviving animals -12 days after starting the test and referred to the total number of test animals treated. The autopsy carried out in each case proved the healing of these animals.

The new compounds obtained according to the process of the invention are superior to known compounds of comparable structure, for instance the N-(p-toluene-sulfonyl) -methyl-urethane, as regards specific efiiciency. .As shown in Table 1 a dose of 0.01 gram/kilogram of N- (p-toluene-sulfonyl)-methyl-urethane causes a surviving total number of l/ 10 only.

The following examples serve to illustrate the invention but they are not intended to limit it thereto:

EXAM'PLE 1.--N- (-METHYL-BENZENE-SULFONYL) (B-METHOXY-ETHYL) -URETHANE (a) 47 grams of para-toluene-sulfonyl-isocyanate are dissolved in 100 cc. of ethyleneglycol-monomethyl-ether, whereby vigorous heating sets in. The solution is still heated for minutes on the steam bath, allowed to cool and cooled with ice. Upon trituration the N-(4-methylbenzene sulfonyl) (B methoxy ethyl) urethane crystallizes out. The w'eld amounts to 40 grams, the melting point of the substance to 141-133 C. By evaporation of the mother liquor a further amount of substance can be recovered. The sulfonyl-urethane can be recrystallized, for example, from methanol, its melting point remaining unchanged. For conversion into the sodium salt 550 grams of N-(4-methyl-benzene-sulfonyl)- (S-methoxy-ethyl)-urethane are suspended favorably .in 5 to 10 times its amount of ethyl alcohol and the equivalent amount of sodium hydroxide solution is added while stirring. Stirring is continued for some hours and the sodium salt formed is filtered off with suction. The yield amounts to 540 grams. .The salt melts at 212-213 C. and is easily soluble in water while showing a neutral reaction. .By distillation under reduced pressure a further amount of substance is obtained which can be purified by conversion into the free urethane.

(b) 460 grams of crude N (4-methyl-benzene-sulfonyl)-methyl-urethane (of about 94% strength). 2000 cc. of glycol-monomethyl-ether and 4 grams of sodium hydroxide or the equivalent amount of sodium-methylate or 202 grams of tn'ethylamine are heated .for 4 hours to smooth boiling. The methyl alcohol formed is slowly distilled ofi through a descending cooler with high neck. The solution is concentrated under reduced pressure and 1.55 liter of glycol-monomethyl-ether is recovered. The

solid residue is dissolved in 4 liters of ammonia solution of about 1% strength by heating. The solution is cooled, filtered and the filtrate is acidified cautiously while stirring. A crystal magma of N(4-methyl-benzene-sulfOnyD-(B-methoXy-ethyI)-urethane is obtained which is sucked off and washed again with water. After drying the crystals melt at 126-127 C. The yield amounts to 476 grams (87% of the theoretical yield). The product can be transformed according to Example 111 into the sodium salt, no further purification being necessary.

(0) 19.3 grams of the sodium salt of para-toluene-sulfonamide and 13.8 grams of finely pulverized potassium carbonate are suspended in 500 cc. of acetone. The reaction mixture is heated to boil and, while stirring, 15.3 grams of chloroformic acid-,S-methoxy-ethyl ester are added dropwise in the course of 2 hours. After a further stirring of 2 hours the mixture is allowed to cool, the precipitate is vacuum filtered, dissolved in cc. of water, filtered and the filtrate is cautiously acidified by means of hydnochloric acid. The crystals of N-(4- methyl benzene sulfonyl) (5 methoxy ethyl)- urethane obtained are vacuum filtered, washed with water and dried. The substance melts at 131-133 C. The yield amounts to 23 grams (89% of the theoretical).

The following table shows a number of N-sulfonyl-(B- methoxy-ethyD-urethanes obtained in good yields from sulfonyl-isocyanates and glycol-monomethyl-ether according to Example 1a, from sulfonyl-methyl-urethanes by reesterification according to Example 1b and from sulfonamides and chloroformic acid-fi-alkoxy-ethyl-ester according to Example 10.

TABLE Melting Method No Product point, according Orystallizing degrees agent Example 1 N-Benzenesulfonyl- 73-74 112 ethanol/water.

(fi-methoxyethyD- urethane.

2 N-(4-ethyl-benzene- 109-111 1b isopropanol.

sulfonyl)-(B-methoxy-ethyl)- urethane.

3 N-(4-Isopropyl-ben- 81-83 10 methanol/ zene-sulfonyl)- water. (B-methoxy-ethyD- urethane.

4 N-(B-Methyl-benzene- 96-98 1c methanol.

sulfonyl)-(fl-methwry-ethyl)- urethane.

5 N-(4-Methoxy-ben- 81-82 It: ethanol/water.

zenesulfonyD-(flmethoxy-ethyl)- urethane.

6 N-(4-Chloro-benzene- 117-119 1a methanol.

sulfonyl)-(fl-methwry-ethyl)- urethane.

7 N-(3-Chlor0-4-methyl- 113-115 1a Do.

benzene-sulfonyD- (fl-methoxy-ethyD- urethane.

8 N(3,4-Dich1oroben- 122-123 10 ethanol/water.

zenesultonyD- (B-methoxyethyburethane.

9 N-(3,4-Dimethyl-ben- 131-132 10 Do.

zenesulfonyD- (fi-methoxyethyburethane.

10."- N-(3,4-Dimethoxy- 90-91 10 Do.

benzene-sulfonyl)- (fimethoxy-ethyhurethane.

11 N-(2-Methy1-6chloro- 130-131 is methanol.

benzene-sulfonyl)- (B- ethoXy-ethyD- urethane.

12.... N-Naphthalene-(2)- -112 112 methanol/water.

sulfonyl-(B-methwry-ethyl)- urethane.

13 N-w-Benzyl-sulfonyl- 86-88 11: acetic ester/ (fl-methoxy-ethyD- cyclohexane. urethane.

14 N-Oyclohexane-sul- 66-68 10 acetic ester.

ionyl-(B-methoxyethyD-urethaue.

15...- N-Butane-sulfonyloi1y 1c (B-methoxy-ethyD- urethane.

dissolved in 200 cc. of glycol-monomethyl ether. The

solution is heated for 8 hours under reflux to boiling.

The excessive solvent is distilled oil under reduced pressure, the residue thus obtained is treated with an aqueous ammonia solution of about 1% strength, any undissolved matter is filtered 011 and the filtrate is acidified by means of hydrochloric acid. The crystalline precipitate of N- (4 methyl benzene sulfonyl) (B methoxy ethyl)- urethane (5 grams) thus obtained is recrystallized from methanol and melts at 131-133 C.

EXAMEVLE 3 25.6 grams of N-(4-methyl-benzene-sulfonyl)-N- acetyl-urea are dissolved in 200 cc. of glycol-monomethyl ether. The solution is heated to boiling for 4 hours under reflux, the excessive glycol-monomethyl ether is distilled off and the residue thus obtained is treated by means of an aqueous ammonia solution of about 1% strength. The filtrate separated from undiss'olved' toluene-sulfonamide is acidified. A crystalline precipitate of N (4 methyl benzene sulfonyl) (B methoxyethyl) -urethane is obtained which is vacuum filtered and dried. The yield amounts to 19 grams. The substance melts at 131-132 C. after having been recrystallized from methanol.

EXAMPLE 4 30.5 grams of N-(4-chloro-benzene-sulfonyl)-N'- butyryl-urea produced by heating of N-(4-chloro-benzene-sulfonyl)-urea and butyric acid anhydride in. the presence of a small amount of concentrated sulfuric acid are dissolved by heating in 200 cc. of glycol-monomethyl ether. The mixture is heated to boil for three hours under reflux. The excessive glycol-monomethyl ether is distilled off under reduced pressure, the residue obtained is treated with an aqueous ammonia solution of 1% strength and filtered. The filtrate is acidified with hydrochloric acid, the crystals obtained are vacuum filtered and dried on clay. grams of N-(4-chloro-benzenesulionyl) -(B-methoxy-ethyl)-urethane are obtained which after having been recrystallized from dilute methanol melt at 116-118 C.

EXAMPLE 5 A mixture consisting of 19.5 grams of the sodium salt of p-toluene-sulfonamide, 12 grams of urea and 38 grams of glycol-monomethyl ether is heated to boiling for 6 hours. The excessive glycol-monomethyl ether is distilled off under reduced pressure, the residue obtained is treated with an ammonia solution of about 1% strength, filtered and the filtrate is acidified by means of hydrochloric acid. The crystals of N-(4-methyl-benzene-snlfonyl)-(6-methoxy-ethyl')-urethane obtained are vacuum filtered and dried. The yield amounts to 4 grams; after recrystallization from methanol the substance melts at 131133 C.

8 EXAMPLE 6 33.4 grams of N-(4-methyl benzene-sulfonyl)-N-diphenyl-urea are dissolved in 250 cc. of glycol-monomethyl ether and heated to boil for 4 hours under reflux. The excessive solvent. is distilled off under reduced pressure and the residue is treated with an aqueous ammonia solution of about 1% strength. The filtrate is acidified, the N (4 methyl-benzene-sulfonyl)-methoxy-ethyl-urethane is sucked oil and recrystallized from methanol. Melting point 131-133" C.

We claim:

1'. A compound of the group consisting of sulfonyl urethanes of the general formula wherein R is a member of the group'consisting of phenyl groups of the formula (R and R being members of the group consisting of hydrogen, chlorine, methoxy, and alkyl groups containing from one to three carbon atoms), fl-naphthyl, benzyl, cyclohexyl and butyl groups; and R represents an alkyl group containing up to four carbon atoms; and nontoxic basic salts of these compounds.

2. The compound of the formula 3. The compound of the formula CH--SONHCOO-CHrCH2OCH: or. 4. The compound of the formula CHa 5. The compound of the formula 6. The compound of the formula 7. A solution eifective on oral administration in the treatment of poultry coccidiosis, said solution containing from 0.2 to 0.3% of a non-toxic basic salt of a sulfonyl urethane of the general formula wherein R is a member of the group consisting of phenyl groups of the formula (References 011 following page) 10 OTHER REFERENCES Herrick et al.: Am. J. Vet. Res., The Experimental References Cited in the file of this patent UNITED STATES PATENTS 2 907 693 Price et a1 O 6 195 Use of Organic Sulfur Compounds for the Prevention of k 1 I 1 FOREIGN PATENTS 5 Cecal Cocc1d1os1s 1n 0111c ens January 9 pp 1 7 122,777 Sweden Dec. 27, 1944 845,042 Germany July 28, 1952 

7. A SOLUTION EFFECTIVE ON ORAL ADMINISTRATION IN THE TREATMENT OF POULTRY COCCIDIOSIS, SAID SOLUTION CONTAINING FROM 0.2 TO 0.3% OF A NON-TOXIC BASIC SALT OF A SULFONYL URETHANE OF THE GENERAL FORMULA 